The present invention relates to compositions and methods for treating acute mountain sickness.
It is well known that the energy coinage of the cell is adenosine triphosphate (ATP). During anabolism, the energy derived from the metabolism of nutrients is transferred to high energy phosphate bonds of ATP. The energy in these bonds is expended during the energy consumption phase. An important and xe2x80x9ccostlyxe2x80x9d expenditure, in which ATP is rapidly cycled, is that required for muscular contraction.
The energy buildup steps occur within the muscle cell during two basic processes. Oxidative phosphorylation replenishes ATP by the breakdown of circulating fatty acids, glucose and intramuscular glycogen and triglycerides. Anaerobic phosphorylation provides ATP from creatine phosphate, circulating glucose and intramuscular glycogen via kinase reactions such as the myokinase reaction.
In the synthesis of ATP via the nucleotide salvage pathway, the nucleotide precursors that may be present in the tissue are converted to AMP and further phosphorylated to ATP. Adenosine is directly phosphorylated to AMP, while xanthine and inosine are first ribosylated by 5-phosphoribosyl-1-pyrophosphate (PRPP) and then converted to AMP. Ribose is found in the normal diet only in very low amounts, and is synthesized within the body by the pentose phosphate pathway. In the de novo synthetic pathway, ribose is phosphorylated to PRPP, and condensed with adenine to form the intermediate adenosine monophosphate (AMP.) AMP is further phosphorylated via high energy bonds to form adenosine diphosphate (ADP) and ATP. During energy consumption, ATP loses one high energy bond to form ADP, which can be hydrolyzed to AMP. AMP and its metabolites adenine, hypoxanthine and inosine are freely diffusible from the muscle cell and may not be available for resynthesis to ATP via the salvage pathway.
In U.S. Pat. No. 4,719,201, it is disclosed that when ATP is hydrolyzed to AMP in cardiac muscle during ischemia, the AMP is further metabolized to adenosine, inosine and hypoxanthine, which are lost from the cell upon reperfusion. In the absence of AMP, rephosphorylation to ADP and ATP cannot take place. Since the precursors were washed from the cell, the nucleotide salvage pathway is not available to replenish ATP levels. It is disclosed that when ribose is administered via intravenous perfusion into a heart recovering from ischemia, recovery of ATP levels is enhanced.
The availability of PRPP appears to control the activity of both the salvage and de novo pathways, as well as the direct conversion of adenine to ATP. Production of PRPP from glucose via the pentose phosphate pathway appears to be limited by the enzyme glucose-6-phosphate dehydrogenase (G6PDH). Glucose is converted by enzymes such as G6PDH to ribose-5-phosphate and further phosphorylated to PRPP, which augments the de novo and salvage pathways, as well as the utilization of adenine. The addition of ribose bypasses this rate limiting enzymatic step.
Many conditions produce hypoxia. Such conditions include acute or chronic ischemia when blood flow to the tissue is reduced due to coronary artery disease or peripheral vascular disease where the artery is partially blocked by atherosclerotic plaques. Transient hypoxia frequently occurs in individuals undergoing anesthesia and/or surgical procedures in which blood flow to a tissue is temporarily interrupted. Peripheral vascular disease can be mimicked in intermittent claudication where temporary arterial spasm causes similar symptoms.
Persons encountering high altitudes or the effective high altitude conditions of air travel, may become hypoxic. They are additionally subjected to low atmospheric pressure. The combination of these two conditions results in Acute Mountain Sickness (AMS). Headache is perhaps the most common symptom of AMS. Headache may be accompanied by lethargy and in extreme cases, potentially fatal cerebral edema. Lung tissue is also affected. Shortness of breath is common and potentially fatal pulmonary edema can occur. Many subject experience nausea. If the symptoms are severe, the person must be taken immediately to lower altitudes and may require hospitalization. If the symptoms are mild, the person may choose to tolerate the discomfort.
A continuing need exists for compositions and methods to alleviate or prevent the symptoms of acute mountain sickness.
The present invention provides compositions for, and methods to, alleviate or prevent the symptoms of acute mountain sickness, which include headache, nausea, lethargy and pulmonary edema with associated shortness of breath and cough. It is believed that the present compositions and methods allow mammals to tolerate situations in which, absent the present compositions and methods, the mammal would experience the onset of symptoms of AMS. The preferred compositions include D-Ribose alone or, optionally, in combination with other energy pathway intermediates, oxygenating substances or pharmaceuticals in pharmaceutically acceptable carriers.
It is here shown that the administration of ribose will alleviate or prevent the symptoms of AMS. Ribose is preferably administered before and during exposure to high altitudes or simulated high altitudes. Preferably, ribose is administered fifteen minutes before exposure to high altitude and two or three times a day until the subject is acclimated to high altitudes. The usual subject becomes acclimated in about five days and ribose can be discontinued at that time. If symptoms re-occur, ribose administration should be re-instituted. Many subjects may choose to take ribose throughout their stay at high altitudes. Ribose is administered in single doses of 0.5 to 30 grams, preferably in doses of three to ten grams, and most preferably in a dose of five grams. The ribose can be administered in any convenient form, such as dissolved in water, added to a soft drink, sprinkled on dry food or incorporated into bars.
The present invention provides a method of alleviating the symptoms of acute mountain sickness (AMS) of a human, by the oral, intravenous or peritoneal administration of and effective amount of ribose to said human. AMS commonly occurs in persons going abruptly from near sea level to a higher elevation. Depending on individual susceptibility, AMS can occur at relatively low altitudes. Persons who are exposed to, for example, carbon monoxide from smoking, or persons with preexisting conditions such as asthma are among those groups that are particularly susceptible to AMS. Altitudes above about 1,000 meters are at significantly lower oxygen tension and atmospheric pressure than at sea level and such more susceptible persons may begin experiencing AMS at this altitude. At altitudes between 1,500 and 3,000 meters, up to 25% of unacclimatized travelers experience AMS. At higher altitudes, both the incidence and severity of AMS increase.
AMS is characterized by a constellation of symptoms. Headache is the main symptom. Nausea, vomiting, dyspnea, insomnia, lethargy, loss of energy, impaired cognition and balance. The onset of symptoms typically occurs within hours to three days after arrival at the high altitude. These symptoms may resolve after several days, but can lead to fatal conditions of cerebral edema and pulmonary edema. Even those experiencing no or minimal symptoms at rest will be more affected if they attempt to exercise.
Travelers who are able to acclimatize gradually, preferably at several stages of increasing altitude, are less affected by AMS. If slow acclimatization is not possible, several medications have been used for the prevention or amelioration of AMS. Acetazolamide is a carbonic anhydrase inhibitor, which creates a metabolic acidosis due to a renal loss of bicarbonate and an inhibition of red blood cell enzymes with a retention of carbon dioxide. If acetazoamide is taken daily, starting three days before reaching altitude, sleep is improved, exercise performance is improved and higher altitudes can be tolerated. Dexamethasone is a catabolic steroid that is effective in reducing vasogenic cerebral edema. It has been found to reduce the symptoms of AMS due to exposure to very high altitudes. Nifedipine, a calcium-channel blocker, may prevent pulmonary problems. The usefulness of these two agents at intermediate altitudes is unclear.
Many persons travel to high altitudes expressly for the purpose of sports, such as skiing and golf. Others are exposed to airplane cabin pressures that are equivalent to altitudes of 2,000 to 4,000 meters for flights as long as eight to twelve hours. All of these subjects would benefit from an easily obtainable, non-prescription agents that would enable them to exercise more comfortably without incurring the headache, lethargy or more severe symptoms of AMS. It has been found as a preliminary result that various persons exercising at high altitudes felt more energetic and did not have AMS when ingesting ribose.
It must be cautioned that persons cannot rely on the compositions and methods of this invention to prevent or give total relief to AMS. If symptoms are severe, it is imperative to evacuate the person to lower altitudes and professional medical care.
For the purpose of describing this invention, the following terms have the following meanings:
1. xe2x80x9cRibosexe2x80x9d means a monosaccharide, including but not limited to, ribose, and any 5-carbon precursor of ribose, D-ribose, ribulose, xylitol and xylulose.
2. xe2x80x9cHypoxiaxe2x80x9d means any state in which the tissue oxygen saturation is reduced to a less than optimal level. Hypoxia includes anoxia, ischemia and poisoning with toxic agents such as carbon monoxide and cyanide which interfere with oxygen utilization. Hypoxia may be chronic as in congestive heart failure, coronary artery disease, peripheral vascular disease or pulmonary dysfunction, or transient as in anesthesia, surgical procedures or exposure to high altitudes.
3. xe2x80x9cHypoxic thresholdxe2x80x9d is that basal level where oxygen saturation of tissues is less than optimal. A raised hypoxic threshold increases tolerance to situations which would otherwise result in hypoxia.
4. xe2x80x9cIschemiaxe2x80x9d is that state of hypoxia caused by reduced circulation of blood to tissue.
5. xe2x80x9cAcute mountain sicknessxe2x80x9d (AMS) is the condition brought on exposure by low oxygen tension combined with low atmospheric pressure. AMS occurs when mammals are brought suddenly to high altitudes, without acclimatization. AMS can also occur on long airplane flights which simulate high altitude.
In co-pending patent application Ser. No. 09/290,789 (the xe2x80x9c""789 Applicationxe2x80x9d), now U.S. Pat. No. 6,159,942, the teaching of which is hereby incorporated by reference, it is disclosed that administration of D-ribose increases the energy level of mammals by stimulating the synthesis of ATP. Examples therein show that ATP levels in the skeletal muscle of healthy mammals under normal conditions of oxygen availability increase upon ribose administration and that the increase is correlated with an increase in performance and activity levels. It is also shown that administration of D-Ribose provides some benefit even to patients with coronary artery disease.
The invention described in the parent to this application, U.S. patent application, Ser. No. 09/406,266, filed Sep. 24, 1999, now U.S. Pat. No. 6,218,366 the teaching of which is hereby incorporated, was based on the discovery that administration of ribose can also increase the tolerance of tissue to low oxygen availability, that is, to hypoxia. In patients with ischemic heart disease, regions of the heart may be poorly perfused, dysfunctional, but still viable. Myocardial ischemia limits blood flow and therefore the available supply of oxygen. This limited availability of oxygen affects oxidative metabolism, which ultimately negatively affects the production of ATP, essential for maintenance of contractility and cellular integrity. Varied states of ischemia exist. However, either transient or chronic ischemia may result in partial reduction of myocardial ATP with subsequent impairment of contractile function, which can lead to heart failure but not cell death.
Therapeutic intervention is variable and must be tailored to each patient. Non-surgical therapies may offer a primary mode of treatment. The first line of action includes angiotensin-converting inhibitors, digoxin and diuretics. So-called inotropic agents such as dobutamine, arbutamine, dopamine, amrinone and milronine, which increase stroke volume and cardiac output, have been universally used for treatment of cardiac dysfunction, which can be manifested by edema, dyspnea, pulmonary congestion and organ hypoperfusion. Many previous studies have investigated the use of ribose in healthy animals such as dogs, rats and swine that have been subjected to ischemic insult. While such studies may suggest therapies for humans with cardiovascular disease, Energy and oxygen availability can each independently influence tissue integrity and function. Although ribose has been shown to enhance energy levels under conditions of normal oxygen availability, the present invention surprisingly shows that when ribose is present, tissue can endure low oxygen availability while still maintaining normal function, without being subjected to the deleterious effects due to low oxygen. Even if energy is available in sufficient quantities, but oxygen is low, adverse effects may still occur in the hypoxic tissue. These effects include pH changes, imbalance in intermediate metabolites and the like. In other words, ribose ameliorates the effects of hypoxia, that is, it raises the hypoxic threshold.
Many patients suffering from xe2x80x9csilentxe2x80x9d cardiovascular disease, that is, such patients are unaware of their condition of chronic hypoxia. The treadmill test has been extensively used to raise the oxygen demand of the heart and uncover the low hypoxic threshold. However, treadmill testing may not be the test of choice in all situations. Dobutamine has been found particularly useful for simulating exercise in patients with coronary artery disease. The infusion of dobutamine produces a stressful myocardial condition similar to that produced by exercise, while the patient is in a controlled hospital setting, with intravenous infusion, in which intervention is readily available. It is theorized that dobutamine increases myocardial stroke volume and cardiac output while reducing ventricular volume and mitral regurgitation due to its vasodilating effects. Because of these multiple effects, dobutamine has been investigated extensively as an agent to increase sensitivity in identifying segmental wall motion activity by echocardiography.
One of the causative factors of AMS is hypoxia and some of the symptoms of AMS are common to those of hypoxia at sea level. It may be expected therefore that the administration of ribose would alleviate lethargy. However, hypoxia does not normally cause headache, cerebral edema, nausea and pulmonary edema. The present invention is directed to amelioration or prevention of the symptoms of AMS, wherein the stress of low oxygen tension is compounded by low atmospheric pressure, which deleteriously affects breathing, leading to pulmonary edema with accompanying cough and edema. The following examples illustrate but are not intended to limit the invention.